Cannabis and its derivatives have long been used for medicinal purposes. The major active ingredient of cannabis, also known as marijuana, is Δ9-tetrahydrocannabinol (THC). Studies on the effects of THC has led to the discovery of an endogenous system of ligands that are involved in many physiological actions including immune system responses in humans. Two cloned cannabinoid receptors have been identified, CB1 and CB2. The CB1 receptor is expressed primarily on neurons in the brain but is also found to a lesser degree in peripheral tissues such as the vasculature and immune cells. Although the CB2 receptor is found in the brain, it is found primarily on cells and tissues of the immune system including, spleen, thymus and tonsils. Activation of CB2 receptors has been shown to modulate the immune system.
Cannabinoids, acting at CB2 receptors, likely exert their immunosuppressive effects by one or more of several ways, including, but not limited to: 1) inducing apoptosis or programmed cell death in immune cells, 2) inhibiting cell proliferation, 3) inhibiting cytokine and chemokine production and 4) inducing regulatory T cells. The apoptotic properties of THC on immune cells has been well studied. For instance, in vivo administration of THC, an agonist at CB1 and CB2 receptors, leads to significant cell death of T cells, B cells, dendritic cells and macrophages in disease models using mice (McKallip R J, Lombard C, Martin B R, Nagarkatti M, Nagarkatti P S. (2002) Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther 302(2):451-65). However, the inventors have demonstrated that both THC and anandamide, an endogenous cannabinoid, induce dose-related immunosuppression in both the primary and secondary in vitro plaque-formation cell assays of antibody formation, a result that is not due to apoptosis. Pretreatment with a selective CB2 receptor antagonist blocks immunosuppression in mouse splenocytes while pretreatment with a selective CB1 receptor antagonist potentiated the in vitro effect at certain doses, suggesting that THC and anandamide mediate immune function effects through the CB2 receptor. In addition, these results demonstrate that both exogenous and endogenous cannabinoids exert their effect on the immune system through CB2 receptors.
It has been shown that broad spectrum cannabinoid agonists have potential as therapeutic agents, however, their medicinal use may be limited because of use and abuse. For example, one of the drawbacks of using marijuana, a CB1/CB2 receptor agonist, is the resulting psychotropic effects due to CB1 receptor activation. Cannabinoids that selectively target CB2 receptors, and thus, the immune system, have great clinical potential as therapeutic agents in the treatment of graft rejection since they are expected to have little or no CB1 receptor activity (i.e. psychotropic effects).
Current immunosuppressant therapies used to prevent or block tissue rejection in organ transplantation are associated with significant untoward effects. For example, toxicity with chronic tacrolimus use is associated with post-transplantation diabetes mellitus (PTDM) due to the death of pancreatic islet cells, and also with kidney damage. Tacrolimus and rapamycin use may induce hyperkalemia. In addition, rapamycin may cause encephalopathies and other central nervous systems deficits including tremors and headache, as well as hypertension and hirsutism. Thus, there is an unmet need for definitive novel methods and/or therapies for blocking graft rejection in humans.